Technical Field
This invention generally relates to inhibitors of necrosis and methods for their use and preparation. The compounds, and compositions comprising the same, can be used in methods for preventing and/or treating diseases involving cell death and/or inflammation.
Description of the Related Art
Programmed necrotic cell death, also called necroptosis, is a form of cell death in which various stimuli such as TNFα, certain toll-like receptor (TLR) agonists, and ischemia can induce cellular necrosis. Necroptosis is a highly inflammatory form of cell death and is thought to be an important contributor to pathology in multiple degenerative and inflammatory diseases. These diseases include neurodegenerative diseases, stroke, coronary heart disease and myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and others.
Necrosis is characterized by cell membrane and organelle disruption, cell swelling and mitochondrial impairment, followed by cell lysis (Syntichaki, P.; Tavernarakis, N. EMBO Rep. 2002, 3(7), 604-609; Martin, L. J., Al-Abdulla, N. A.; Brambrink, A. M.; Kirsch, J. R.; Sieber, F. E.; Portera-Cailliau, C. Brain Res. Bull. 1998, 46(4), 281-309). Also, cell lyses typically are accompanied by an inflammatory response. Some of the underlying biochemical events in this process are now understood, and the activity of receptor interacting protein kinase 1 (RIP1 kinase) has been shown to be important for cells to undergo necroptosis. Furthermore, RIP1 kinase activity is also known to promote the release of inflammatory mediators such as TNF alpha from cells which can induce inflammation and also promote further necroptosis (Christofferson, D. E., Li, Y., Hitomi, J., Zhou, W., Upperman, C., Zhu, H., Gerber, S. A., Gygi, S., Yuan, J. Cell Death Dis. 2012, 3, e320). Therefore, identifying and preparing low molecular weight molecules that prevent necrotic cell death and/or inflammation by inhibiting RIP1 kinase or by other mechanisms can provide useful compounds for therapeutic intervention in diseases characterized by necrotic cell death and/or inflammation.
Small molecules inhibitors of cellular necrosis have been investigated. For example, U.S. Pat. No. 7,491,743 (“the '743 patent”) and U.S. Patent Publication No. 2012/012,889 describe indole-substituted hydantoin molecules as inhibitors of necrosis. The compounds disclosed in these publications include chiral hydantoin moieties linked to an indole moiety via a methylene bridge. Although various preparations for such compounds have been proposed, each of these preparations suffer from various disadvantages such as achiral products, linear synthetic strategies, long and/or low yielding synthetic routes and/or use of enzymes for resolution of racemic products or reagents. Accordingly, none of the currently available preparation methods are useful for large scale production of the indole-substituted hydantoin compounds.
While progress has been made, there remains a need in the art for improved methods for preparation of inhibitors of cellular necrosis as well as improved compounds for preventing and treating diseases involving cell death and/or inflammation. The present disclosure provides this and related benefits.